Project Summary/Abstract Multiple Sclerosis (MS) is the second leading cause of disability among young adults and the second most costly chronic disease in North America. MS autoimmune neuropathology is manifested by attacks of muscle weakness, loss of coordination, fatigue, visual disturbances, bladder dysfunction and cognitive impairment. Onset of MS occurs when immune cells, or lymphocytes, cross the brain protective ?fence? known as the blood- brain barrier (BBB), a process known as immune extravasation. Previous studies had found that normal human brain and mouse spinal cord tissues exhibit ablumenal localization of the chemokine CXCL12 at their vasculature. However, specimens from MS patients and mice with experimental autoimmune encephalomyelitis (EAE) exhibit relocation of CXCL12 to the lumenal surfaces of vessels, known as change in apicobasal polarity. This alteration in CXCL12 expression had been identified to facilitate immune extravasation, therefore causing MS and EAE. It is also accepted that immune extravasation correlates with increased in BBB permeability. Although, BBB permeability is triggered by vascular endothelial growth factor A (VEGF-A) the mechanisms that link VEGF to changes in CXCL12 and immune extravasation are still elusive. Cytokines are known to be involved in many cellular responses. One cytokine, interleukin 20 (IL-20), induces cellular responses through the receptor IL-20RB. Dysregulated IL-20 signaling is also implicated in autoimmune pathologies including rheumatoid arthritis, atherosclerosis, and psoriasis. Our preliminary data demonstrate that IL-20RB signaling plays an important role in EAE, although the specific mechanism has not been established. Our central hypothesis is that IL-20 plays a key role in MS by signaling via IL-20RB to induce VEGF activity, enhances BBB permeability and consequently facilitates immune extravasation. We will test this hypothesis via the following specific aims: Aim 1: Identify the cellular components of the BBB that mediate IL-20 signaling during EAE. Aim 2: Determine if IL-20 signaling through IL-20RB is required for pathogenesis in mouse model of MS. Aim 3: Determine if IL-20 via IL-20RB modulates BBB permeability and apicobasal polarity via relocation of CXCL12. Results of the proposed experiments will further our understanding of the relevance of the BBB in the neuropathogenesis of EAE and MS. This will help the design of disease-modifying drugs for MS that are both neuromodulatory and non-immunosuppressive.